AB0257 GENETIC EVIDENCE REVEALS A CAUSAL ROLE BETWEEN LEUKOCYTE COUNTS AND THE RISK OF RHEUMATOID ARTHRITIS
Authors: Y. Zhang, Q. Qiu, J. Hu, J. Hou, Q. Yu, P. F. He, X. Li, S. X. Zhang
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Accumulating inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). However, no relevant study indicates whether there is insidious causation between leukocyte count (LC) and the risk of RA. Traditional observational studies were susceptible to bias from confounding and reverse causation. It was necessary to estimate an exact correlation between LC and the risk of RA. <h3>Objectives</h3> This study aimed at evaluating the correlation between LC and the risk of RA by performing two-sample Mendelian Randomization(MR). <h3>Methods</h3> This study selected single nucleotide polymorphism (SNPs) associated(p&lt;5e<sup>-8</sup>) with exposure (LC) from a genome-wide association study (GWAS), which included 171846 European ancestry participants and wiped off confounding factors. The association estimates of these SNPs with the risk of RA were obtained from another GWAS, including 14361 RA cases and 42923 controls. Upon SNPs were compared with SNPs related to the risk of RA and performed harmonization analysis to wipe off the irrelevant or inconsistent site SNPs. Ultimately, the remaining SNPs were selected as instrument variables(IVs). Then, we utilized two-sample Mendelian randomization (MR) to evaluate whether LC was causally associated with the risk of RA. Furthermore, Cochran's Q test, MR pleiotropy residual sum and outlier (MR-presso), and leave-one-out analysis were performed as a sensitivity test. <h3>Results</h3> A total of 70 independent SNPs were selected as IVs in the MR analysis of total WBC. Higher leukocyte counts were associated with a higher risk of RA (OR=1.025,95% CI: 0.998-1.053,p-value=0.038) by the IVW method (<b>Figure 1</b>). The MR-Egger regression test did not reveal any evidence of directional pleiotropy (intercept = -0.0002, stand error (SE) = 0.008, p = 0.981). In addition, leave-one-out sensitivity analysis showed similar findings, which further emphasized the effectiveness and stability of the causation. However, in the Cochrane's Q test, it turned out [Cochrane's Q statistic= 69, p-value=3.472e<sup>-20]</sup>, suggesting heterogeneity exists. For this reason, the processed steps were rechecked, and finally got, the conclusion that heterogeneity is produced from sysmaticness. <h3>Conclusion</h3> This study indicated the insidious causation between LC and the risk of RA. Further studies are warranted to determine how related pathways may contribute to the unnormal LC to promote the comprehension of the pathology of the happening of RA and access more therapeutic methods. <h3>References</h3> [1] Astle, W.J., et al., <i>The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.</i> Cell, 2016. <b>167</b>(5): p. 1415-1429.e19. [2] Ha, E. and S.C. Bae, <i>Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci.</i> 2021. <b>80</b>(5): p. 558-565. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.